The overall goal of this project is to systematically evaluate prodrug strategies for targeting larger amounts of various antiviral compounds to important tissue reservoir of disease: the lymphatic system in AIDS and the liver in hepatitis B. The investigators intend to identify optimal prodrug strategies for targeting the lymphatic tissue reservoir of HIV and to find the optimal liposome formulations and mode of administration by studying lymph node and tissue distribution of radiolabeled antiviral prodrugs. Optimized prodrug strategies will be tested in animal models of hepatitis B, specifically the woodchuck hepatitis model, and in models of retro viral disease in mice. Additionally the applicants plan to systematically evaluate various lipid prodrug HBV antivirals in vitro in 2.2.15 cells to find the most active chemical forms. The investigators have already found that certain lipid analogs of acyclovir and azidothymidine are much more active than the free nucleotides in 2.2.15 cells. The biologic and metabolic basis for the greatly increased activity will be evaluated to aid in design of better antiviral agents. Finally, the researchers will explore the activity of the optimized liver-targeted lipid prodrug antivirals in woodchuck HBV; and their toxicity will be evaluated in rodents.